Deuterated 1,1-difluoro-2,2-dihaloethyl difluoromethyl esters

ABSTRACT

Deuterated halo ethers useful as anesthetics and having lower toxicity than undeuterated analogues further including compositions, and methods of use.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a divisional application of copending applicationSer. No. 882,498 filed March 1, 1978, which is a continuation-in-part ofcopending application Ser. No. 803,926 filed June 6, 1977, nowabandoned.

BACKGROUND OF THE INVENTION

Various 1,1-difluoro-2,2-dihaloethyl difluoromethyl ethers have beendescribed in the prior art and are known for use as inhalationanesthetics. See U.S. Pat. Nos. 3,469,011; 3,527,811; 3,527,812; and3,527,813. The most commonly used is the compound1,1,2-trifluoro-2-chloroethyl difluoromethyl ether also known asenflurane. Although the metabolic pathways of enflurane have not beendefined, it is known the compound is metabolized in the body to produceinorganic fluorides in the blood which can cause renal dysfunction. SeeBarr et al., J. Pharmacol. Exp. Therap. 188, 257 (1974); Mazze et al.,Anesthesiology 46, 265 (1977); and Eichhorn et al., Anesthesiology 45,557 (1976). In addition, elevated levels of serum bromides released frommetabolized material containing bromine is responsible forpost-anesthetic depression.

SUMMARY OF THE INVENTION

The present invention is directed to novel deuterated analogues of theknown 1,1-difluoro-2,2-dihaloethyl difluoromethyl ethers; the deuteratedanalogues have the general formula: ##STR1## wherein X and X' representa halogen selected from the group consisting of chloro, fluoro, andbromo with the proviso that when X is chloro X' is chloro or fluoro, andfurther when X is fluoro X' is bromo or chloro.

The present invention is also directed to a method of anesthetizing ananimal, preferably a mammal, which comprises administering by inhalationan effective anesthetizing amount of a compound falling within the abovegeneral formula as a general inhalation anesthetic. As used herein, theterm "animal" refers to an inhalation anesthetic susceptible animal.

The present invention is also directed to an anesthetic compositionwhich comprises the minimum alveolar concentration of a compound fallingwithin the scope of the present invention in combination with aninnocuous gas vaporization medium and/or in combination with otheranesthetics such as, for example, nitrous oxide. In anesthetizing ananimal using the compounds, methods, and compositions described herein,the compound is usually administered by vaporizing the compound in thepresence of an innocuous gas vaporization medium such as, for example,helium, nitrogen, oxygen, or various mixtures thereof. As used herein,the term "minimum alveolar concentration" refers to the effectiveconcentration of the anesthetic or anesthetic combination required toproduce the desired degree or anesthesia in the animal. The particularminimum alveolar concentration depends on factors well known in the artsuch as the animal to be anesthetized, the particular compound employed,etc.

Thus, it is seen three compounds fall within the scope of the presentinvention. They are as follows: ##STR2## hereafter referred to asmonodeuterated enflurane or 1,1,2-trifluoro-2-chloro-2-deuteroethyldifluoromethyl ether; ##STR3## hereafter referred to as1,1-difluoro-2-deutero-2,2-dichloroethyl difluoromethyl ether; and##STR4## hereafter referred to as 1,1,2-trifluoro-2-bromo-2-deuteroethyldifluoromethyl ether.

The present invention is especially surprising in light of the fact thatthe monodeuterated analogue of methoxyflurane, i.e., the compound1,1-difluoro-2,2-dichloro-2-deuteroethyl methyl ether, is more readilymetabolized in the body to inorganic fluoride than the undeuteratedcompound. Thus, monodeuteration of methoxyflurane on the 2-carbon of theethyl chain actually increases the toxicity of the compound.

DETAILED DESCRIPTION OF THE INVENTION

One method for preparing the 1,1-difluoro-2-deutero-2,2-dihaloethyldifluoromethyl ethers that are the subject of the present invention isby a base catalyzed deuterium exchange involving the hydrogen atom inthe 2-ethyl position of the undeuterated anesthetic molecule. In thismethod the 1,1-difluoro-2,2-dihaloethyl difluoromethyl ether is mixedwith heavy water (D₂ O) in the presence of a strong base catalyst at atemperature and for a time sufficient to replace substantially all ofthe hydrogen in the 2-ethyl position of the anesthetic molecule withdeuterium. Similar procedures are described in JACS 83, 1219 (1961) forthe preparation of deuterated halothane. The hydrogen-deuterium exchangeis an equillibrium reaction, therefore excess heavy water should bepresent to force the reaction in the direction of the deuteratedanesthetic. In general, a ratio of about 10 parts heavy water to about 1part anesthetic on a weight/weight basis will lead to substantiallycomplete deuteration of the 2-ethyl position of the molecule.

The strong base catalyst is generally a soluble hydroxide or alkoxide ofan alkali metal such as sodium or potassium. Alternately, a strong baseion exchange resin, such as for example Dowex^(R) 21K (The Dow ChemicalCo.), may be used to catalyze the reaction. The reaction mixture isallowed to react at a temperature of from about 25° to 150° C., withfrom about 50° to 100° C. being preferred, for a time sufficient toallow substantially all of the hydrogen to be replaced by deuterium onthe anesthetic molecule. In general, the higher the reaction temperaturethe more quickly the exchange is completed. For relatively low boilinganesthetics such as enflurane (about 55° C.) correspondingly longerreaction times are required. To shorten the reaction time a pressurizedreaction vessel may be employed to allow higher reaction temperatures.Phase transfer catalysis may also be used to increase the speed at whichthe reaction occurs.

The following examples will serve to further clarify the presentinvention but are not to be construed as a limitation thereon.

EXAMPLE 1--Preparation of Monodeuterated Enflurane

A 500 ml three-necked flask fitted with a reflux condenser and magneticstirrer was charged with 100 ml of heavy water (D₂ O) having 99.7%deuterium replacing the hydrogen, 5 grams of anhydrous sodium hydroxide,and 145 grams of enflurane. The mixture was heated at reflux (about 55°C.) for about 3 days. The reaction mixture was allowed to cool to roomtemperature. The ether was separated and dried over calcium chloride.The dry ether was distilled through a four inch vigreux column, and thefraction boiling at 56°-57° C. was collected. NMR analysis confirmedthis fraction as 90% deuterated enflurane.

EXAMPLE 2--Preparation of 1,1-Difluoro-2-Deutero-2,2-DichloroethylDifluoromethyl Ether

A reaction vessel similar to that used in Example 1 above was chargedwith 200 ml of heavy water, 10 grams of anhydrous sodium hydroxide, and200 grams of 1,1-difluoro-2,2-dichloroethyl difluoromethyl ether. Thereaction mixture was refluxed at about 76° C. for about 1.5 hours.Bromine was added dropwise to the crude1,1-difluoro-2-deutero-2,2-dichloroethyl difluoromethyl ether until thered bromine color persisted for several minutes. The resulting mixturewas irradiated with a 275 watt sunlamp during bromine addition. Themixture was washed with dilute sodium hydroxide to remove the residualbromine, dried and distilled. The fraction boiling at 87° C. wascollected. NMR analysis showed this fraction to be 93% CF₂ HOF₂ CCl₂ D.

EXAMPLE 3--Preparation of 1,1,2-Trifluoro-2-Bromo-2-DeuteroethylDifluoromethyl Ether

In the same manner as described in Examples 1 and 2 above, the reactionvessel was charged with 200 ml of heavy water, 10 grams of anhydroussodium hydroxide and 200 grams of 2-bromo-1,1,2-trifluoroethyldifluoromethyl ether. The reaction mixture was heated to reflux (about67° C.) and held at that temperature for about 1.5 hours. The reactionmass was cooled after which the crude ether was separated and dried overcalcium chloride. The dry ether was distilled, and the fraction boilingat about 72°-73° C. was collected. NMR analysis showed this fraction tobe greater than 96 percent 1,1,2-trifluoro-2-bromo-2-deuteroethyldifluoromethyl ether.

EXAMPLE 4

Metabolism studies for the presence of inorganic fluorides following theuse of monodeuterated enflurane and enflurane were carried out asfollows. Enflurane and monodeuterated enflurane were vaporized bymetering the liquid compound at a controlled rate into a temperatureregulated vaporization flask held at 150° C. The vapor was swept intothe air inlet of a 30 liter glass exposure chamber at a rate of 6liters/minute. The concentration of the anesthetic in the exposurechamber was monitored by gas-liquid chromatography using direct gassampling loops.

Groups of 8 male Fisher rats (6 months of age, 250-300 grams) wereexposed to room air (controls) and 2.5% volume/volume of enflurane andmonodeuterated enflurane for a period of 3 hours. After exposure, theanimals were removed immediately. All animals were maintained inindividual metabolism cages for 48 hours after exposure. Urine wascollected during each of two 24 hour intervals after exposure. Nodifferences were noted between the anesthetic properties of enfluraneand monodeuterated enflurane.

Urinary volume for each animal was recorded and the urine samples wereassayed for inorganic fluoride using an Orion fluoride electrode.

A comparison of the amount of total inorganic fluoride in the urine ofthe control and test animals is shown in Table 1 below.

EXAMPLE 5

Using essentially the same technique as described in Example 4 above thecompound 1,1,2-trifluoro-2-bromoethyl difluoromethyl ether was comparedto its mono-deuterated analogue prepared according to the method ofExample 3. The rats were exposed to 1.5 percent volume/volumeconcentration of the control anesthetic and its deuterated analogue fora period of 3 hours. No differences were noted between the anestheticproperties of 1,1,2-trifluoro-2-bromoethyl difluoromethyl ether and themono-deuterated analogue.

Urine volume was recorded, and the urine was assayed for inorganicfluoride. The results are shown in Table I. In addition, after 48 hoursthe animals were sacrificed, and the blood was collected. Serum bromideion concentrations were determined using an Orion bromide electrode. Theresults of the bromine determinations are shown in Table II.

EXAMPLE 6

Using essentially the same methods as described in Example 4 thecompound 1,1-difluoro-2,2-dichloroethyl difluoromethyl ether and itsmono-deuterated analogue were compared. Because of the potency of theseanesthetics the rats were exposed to a concentration of only 0.5 percentvolume/volume of the anesthetic and its mono-deuterated analogue. Againno differences in anesthetic properties were noted between1,1-difluoro-2,2-dichloroethyl difluoromethyl ether and itsmono-deuterated analogue.

The urine was collected and analyzed for inorganic fluorideconcentration. The results are recorded in Table I.

                                      TABLE I                                     __________________________________________________________________________                    Urine Volume ml.                                                                          Urinary Fluoride μM**                                                                  Total Urinary                         Example                                                                            Treatment  24 hrs                                                                              48 hrs                                                                              24 hrs                                                                              48 hrs                                                                              Fluoride nM*                          __________________________________________________________________________         Room Air (Controls)                                                                      9.2 ± 0.8                                                                        10.9 ± 2.6                                                                       0.9 ± 0.4                                                                        1.1 ± 0.2                                                                        20.6 ± 2.7                         4    CF.sub.2 HOCF.sub.2 CClFH                                                                14.8 ± 2.2                                                                       11.0 ± 1.9                                                                       4.3 ± 0.7                                                                        1.6 ±  0.2                                                                        80.7 in  10.1                             CH.sub.2 HOCF.sub.2 CClFD                                                                10.9 ± 1.5                                                                       8.9 ± 1.5                                                                        1.7 ± 0.2                                                                        1.1 ± 0.1                                                                        28.6 ± 4.7                              Room Air (Controls)                                                                      9.1 ± 1.0                                                                        8.5 ± 1.5                                                                        0.7 ± 0.1                                                                        0.8 ± 0.1                                                                        12.7 ± 0.7                         5    CF.sub.2 HOCF.sub.2 CFBrH                                                                12.8 ± 1.4                                                                       8.0 ± 1.5                                                                        10.4 ± 1.9                                                                       3.3 ± 0.7                                                                        156.8 ± 20.9                            CF.sub.2 HOCF.sub.2 CFBrD                                                                11.3 ± 1.9                                                                       7.4 ± 1.0                                                                        2.6 ± 0.9                                                                        1.3 ± 0.1                                                                        37.8 ± 5.8                              Room Air (Controls)                                                                      10.3 ± 2.5                                                                       8.3 ± 2.8                                                                        0.7 ± 0.0                                                                        0.8 ± 0.1                                                                        14.2 ± 3.4                         6    CF.sub.2 HOCF.sub.2 CCl.sub.2 H                                                          14.6 ± 2.3                                                                       10.0 ± 2.1                                                                       1.4 ± 0.2                                                                        1.0 ± 0.1                                                                        30.2 ± 3.6                              CF.sub.2 HOCF.sub.2 CCl.sub.2 D                                                          12.2 ± 1.3                                                                       9.6 ± 1.6                                                                         1.1 ± 0.01                                                                      0.8 ± 0.1                                                                        21.5 ± 2.9                         __________________________________________________________________________     *Inorganic fluoride expressed in nanomoles (nM)                               **Inorganic fluoride expressed as micromolar (μM)                     

                  TABLE II                                                        ______________________________________                                        Treatment       Serum Bromine (millimolar)                                    ______________________________________                                        Room Air (Controls)                                                                           0.53 ± 0.02                                                CF.sub.2 HOCF.sub.2 CFBrH                                                                     1.59 ± 0.70                                                CF.sub.2 HOCF.sub.2 CFBrD                                                                     0.82 ± 0.09                                                ______________________________________                                    

The data indicate that animals treated with the mono-deuterated1,1-difluoro-2,2-dihaloethyl difluoromethyl ethers, that are thesubjects of the present invention, show significantly lowerconcentrations of inorganic fluoride in the urine of the treated animalsthan in the urine of similar animals anesthetized using the undeuteratedanalogues. Likewise animals treated with1,1,2-trifluoro-2-bromo-2-deuteroethyl difluoromethyl ether showed lowerconcentrations of inorganic bromide in the serum than the serum ofanimals treated with undeuterated anesthetic. The most dramaticdifferences were seen in the mono-deuterated enflurane and1,1,2-trifluoro-2-bromo-2-deuteroethyl difluoromethyl ether where adecrease in organic fluoride of 65 percent and 76 percent, respectively,as compared to the undeuterated anesthetics was observed. Although lessdramatic, a significant decrease (29 percent) was also observed for1,1-difluoro-2-deutero-2,2-dichloroethyl difluoromethyl ether.Anesthetic potency coupled with a low release of inorganic fluoride intothe blood make this latter compound the preferred embodiment of theinvention.

We claim:
 1. The process of anesthetizing an inhalation anestheticsusceptible animal which comprises administering an effectiveanesthetizing amount of a compound of the formula ##STR5## wherein X andX' represent a halogen selected from the group consisting of chloro,fluoro, and bromo with the proviso that when X is chloro X' is chloro orfluoro, and further when X is fluoro X' is bromo or chloro, as a generalinhalation anesthetic to said animal.
 2. The process of claim 1 whereinthe compound is administered to the animal by vaporization of thecompound in the presence of an innocuous gas vaporization medium.
 3. Theprocess of claim 1 wherein the compound is1,1,2-trifluoro-2-deuteroethyl difluoromethyl ether.
 4. The process ofclaim 1 wherein the compound is 1,1-difluoro-2-deutero-2,2-dichloroethyldifluoromethyl ether.
 5. The process of claim 1 wherein the compound is1,1,2-trifluoro-2-bromo-2-deuteroethyl difluoromethyl ether.
 6. Theprocess of claim 2 wherein the compound is administered in the presenceof oxygen.
 7. An anesthetic composition comprising an effectiveanesthetizing concentration of a compound of the formula ##STR6##wherein X and X' represent a halogen selected from the group consistingof chloro, fluoro, and bromo with the proviso that when X is chloro X'is bromo or chloro, and an innocuous gas vaporization medium.
 8. Theanesthetic composition of claim 7 wherein the innocuous gas vaporizationmedium contains oxygen.
 9. The anesthetic composition of claim 7 furtherincluding another anesthetic.
 10. The anesthetic composition of claim 7wherein the compound is 1,1,2-trifluoro-2-chloro-2-deuteroethyldifluoromethyl ether.
 11. The anesthetic composition of claim 7 whereinthe compound is 1,1-difluoro-2-deutero-2,2-dichloroethyl difluoromethylether.
 12. The anesthetic composition of claim 7 wherein the compound is1,1,2-trifluoro-2-bromo-2-deuteroethyl difluoromethyl ether.